Alterations in the biosynthesis, secretion, and control of TSH and its subunits occur in patients with disorders of the thyroid-pituitary axis. To define these abnormalities, we must understand the molecular events involved in the biosynthesis of TSH and its subunits. Towards this goal, we have initiated an integrated proposal to study the factors regulating the biosynthesis, secretion, clearance, and metabolism of the thyroid stimulating hormone (TSH) and its alpha and beta subunit in man, in an animal model for human thyroid disease and at the cellular level, in vitro. We will determine the long-term metabolic consequences of slight and variable decreases in the serum concentration of T4 and T3 and concomitant increases of TSH on: (a) cardiovascular system, (b) pituitary function and size (tumor), and (c) breast abnormalities, including breast cancer. We plan to expand our investigations of the unbalanced alpha subunit secretion by pituitary tumors in patients in order to evaluate the efficacy of subunit measurements in early diagnosis and effective therapy. In addition, immunochemical and physicochemical properties of subunits secreted by pituitary tumors will be evaluated to elucidate similarities or differences in the biosynthesis of the glycoproteins from normal and malignant pituitary cells. We have already established that the inbred Buffalo rat is an ideal animal model for human thyroid disease since it has a significant and spontaneous incidence of autoimmune thyroiditis and hypothyroidism, with females greater than males. In addition, this species is an ideal model in which to study the relationships of thyroid disease and breast cancer since both diseases are readily inducible in this animal. We propose an extensive program to study the biochemical mechanisms and control of TSH biosynthesis using an in vitro system derived from a murine TSH producing pituitary tumor to determine intracellular events involved in hormone biosynthesis in the thyrotroph.